New Clinical Recommendations for Genetic Testing?

This post is by Leanne Chukoskie, Ph.D. Leanne earned her Ph.D. at NYU’s Center for Neural Science studying the neural mechanisms that mediate vision during eye movements. During her postdoctoral training at the Salk Institute she studied search behavior in both humans and animals. A family connection as well as the curious manner in which people with autism tend to scan a visual scene led her to work for Autism Speaks as the Assistant Director of Science Communication and Special Projects. Leanne also continues her research as a Project Scientist at UCSD.

Studies from “identical” (monzygotic) twins show that if one twin has autism, the other twin will also have autism about 90% of the time. Because identical twins share 100% of their genes, these data offer the strongest evidence that genetic risk factors are involved in autism. However, those numbers cannot help any particular family discern what the genes or genetic abnormalities that are contributing to their child’s autism.

A new paper in the journal Pediatrics has instigated discussion over the best way to screen patients with autism in clinical settings for genetic mutations. Current practice guidelines recommend that a standard karyotype be performed, which looks at all of the chromosomes to see if there is something clearly amiss like specific chromosomal rearrangements or Fragile X Syndrome. This technique has been in use for some time, and one of its advantages is that this test is readily available and is considered the “standard of care”. The disadvantage, however, is that many individuals with autism have no karyotype-detectable genetic abnormalities and are left uncertain about the genetic contribution to their autism.

Dr. Bai-Lin Wu and colleagues have reported on another technique, chromosomal microarray analysis (CMA) that provides a more in-depth examination of genes and chromosomes. This test has been used in research settings for many years. The benefits of using CMA for clinical practice lies in its sensitivity to detect more subtle duplications or deletions in the genetic code (known as copy number variations or CNVs) that may be too small to be detected with a simple karyotype. The difficulty, however, lies in explaining to families what the “abnormal” findings mean, specifically, if they contribute to autism risk or if their occurrence is coincidental. This is important for families trying to make informed healthcare decisions, especially given the cost of the test (typically over $1000) may not be covered by insurance. Therefore, understanding the clinical implications of these potentially significant genetic findings is going to be a critical next step for clinical geneticists.

Although there is no doubt that learning more about autism susceptibility genes is critical for the field, we have to be very careful not to give parents false hope. CMA analysis may detect genetic differences that current research shows are unassociated only weakly associated with autism. This scenario would provide an inconclusive picture of the genetic contribution to one’s autism risk. On the other hand, for some other genetic differences, the benefit to individuals may be considerable. For example, research has identified an area on chromosome 22, including the Shank3 gene, that has repeatedly been associated with autism. While currently there is no rescue or specific treatment for individuals with this mutation, families that have a child with this particular mutation can support and learn from each other at the Phelan-McDermid Syndrome Foundation (http://www.22q13.org/). Scientists hope that more can be learned from individuals with autism that have known genetic disorders such as Phelan-McDermid Syndrome, Fragile X and Rett Syndromes.

There will always be a lag between research level diagnostics and the translation of that information into a clinical standard of care. Studies like this push the envelope to raise the bar for establishing higher clinical standards and guidelines. We need more research to determine how best to use this information to benefit the families.